Allogeneic islet cell transplantation is a promising therapy for patients who have autoimmune diabetes (Shapiro A M, et al. (2006) N Engl J Med 355:1318-1330.; Ryan E A, et al. (2005) Diabetes 54:2060-2069.; herein incorporated by reference in their entireties). However, as in solid-organ transplantation, robust donor-specific allogeneic responses (Mohanakumar T, et al. (2006) Transplantation 82:180-187.; Campbell P M, et al. (2007) Am J Transplant 7:2311-2317.; herein incorporated by reference in their entireties) necessitate life-long immunosuppression that increases the risk for fatal opportunistic infections. In addition, the currently used immunosuppression regimen has intrinsic β-cell toxicity (Nir T, Melton D A, Dor Y (2007) J Clin Invest 117:2553-2561.; Hyder A, Laue C, Schrezenmeir J (2005) Toxicol In Vitro 19:541-546.; herein incorporated by reference in their entireties). Therefore, a means of establishing donor-specific tolerance to obviate the need for immunosuppression is highly desirable for therapeutic cell or allograft transplantation.
Strategies for inducing alloantigen-specific tolerance include mixed hematopoietic chimerism, costimulation blockade, peripheral T-cell depletion, and induction and expansion of regulatory T cells (Tregs) (Lechler R I, Sykes M, Thomson A W, Turka L A (2005) Nat Med 11:605-613.; herein incorporated by reference in its entirety). Most regimens require myeloablation/cytoreduction and/or blocking antibodies targeting various T-cell signaling components, and these antibodies have significant toxicities. Using Tregs is less toxic, but the main challenge is to obtain sufficient numbers of alloantigen-specific Tregs (Long E T, Wood K J (2007) Front Biosci 12:4042-4049.; Luo X, et al. (2007) Proc Natl Acad Sci USA 104:2821-2826.; herein incorporated by reference in their entireties).
Previous studies have shown that i.v. injection of antigen-pulsed splenic antigen-presenting cells (APCs) chemically fixed with 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (ECDI) is a powerful and safe method to induce antigen-specific T-cell tolerance in vivo (Kennedy M K, et al. (1990) J Immunol 144:909-915.; Tan L J, Kennedy M K, Miller S D (1992) J Immunol 148:2748-2755.; herein incorporated by reference in their entireties). Specifically, myelin peptide-coupled, ECDI-fixed syngeneic APCs could effectively ablate induction and progression of experimental autoimmune encephalomyelitis (EAE), a murine Th1/17-mediated model of multiple sclerosis (Vanderlugt C L, et al. (2000) J Immunol 164:670-678.; herein incorporated by reference in its entirety). Recent work using this tolerance method has defined the importance of cross-tolerance via host APCs and the role of specific Tregs (Kohm A P, Carpentier P A, Anger H A, Miller S D (2002) J Immunol 169:4712-4716.; Kohm A P, et al. (2005) J Immunol 174:4525-4534.; Miller S D, Turley D M, Podojil J R (2007) Nat Rev Immunol 7:665-677.; herein incorporated by reference in their entireties). This protocol also is effective in preventing and treating autoimmune diabetes in nonobese diabetic (NOD) mice (Fife B T, et al. (2006) J Exp Med 203:2737-2747.; herein incorporated by reference in its entirety).
What is needed are more effective methods of inducing donor cell tolerance in a recipient receiving donor cells or an allograft.